This project will continue studies on the use of pharmacological inhibitors of fatty acid synthase (FAS) for lung cancer treatment in both the setting of clinical trials (with correlative markers) and in the laboratory setting for refinement of this treatment strategy. Under current funding from the SPORE mechanism, we have 1) confirmed that FAS is a promising target for lung cancer treatment, 2) identified a class of pharmacological compounds that can selectively inhibit FAS activity without significantly affecting fatty acid oxidation (with associated anorexia), and 3) demonstrated that these compounds effectively inhibit growth of human lung cancer xenograftsand mouse lung tumors, without causing significant toxicity. Furthermore, our work has evaluated pharmacokinetics of a FAS inhibitor and demonstrated the ability to administer these compounds orally, which support our expectations of moving this project to clinical trials for lung cancer treatment. Finally, experiments conducted during the initial funding period have demonstrated the ability of positron emission tomography (PET) imaging to monitor response to FAS inhibitors, and also found additive or synergistic effects when FAS inhibitors are used in combination with other chemotherapeutic agents. In the first specific aim of this proposed project, we will evaluate a pharmacological inhibitor of fatty acid synthase in early stage clinical trials. We expect to initiate a phase 1 trial in the current funding period, and phase 2 clinical trails in the proposed funding period. Both phase 1 and phase 2 clinical trials will include monitoring patients with the candidate markers of response developed in Specific Aim #2 (including FDG/PET imaging), in addition to standard measures of patient response. Specific aim #2 will determine the effect of fatty acid synthase inhibitors on signal transduction pathways and cellular metabolism in pre-clinical models of lung cancer, to identify potential markers for predicting and monitoring response to these agents. As noted above, these markers will be applied to the clinical trial setting. Finally, in specific aim #3, we will evaluate the potential role for fatty acid synthase inhibitors in combination cancer therapy. We will evaluate potential additive or synergistic effects of combining FAS-inhibiting compounds with conventional chemotherapeutic agents for lung cancer, as well as with novel agents that target specific signal transduction pathways. Understanding how a FAS inhibitor can be effectivelycombined with other agents will provide a framework for effective use of this compound in the clinical setting. Relevance to Public Health: This project will develop a new therapeutic strategy for lung cancer treatment.